Patients with diabetes would benefit from therapies that increase functional ?-cell mass. ?-cells naturally adapt to increased metabolic demand and insulin resistance by expanding their functional mass, a process that decreases with aging. We have recently demonstrated a critical role for Myc in adaptive expansion of functional ?-cells in young but not old mice. Despite multiple studies describing the effect of Myc overexpression in beta cells, there is a knowledge gap about how this crucial anabolic transcription factor perceives and responds to nutrients and increased insulin demand in its native context. How do nutrients regulate Myc expression in ?-cells? How does Myc participate in the regulation of GSIS and mitochondrial function in the ?-cell, how does Myc fail to increase adaptive proliferation in aged ?-cells or will targeted demethylation of specific Myc binding sites increase ?-cell proliferation in metabolically-stressed aged ?-cells? These important questions about the physiological role of Myc in the ?-cell need to be answered to advance our knowledge and find therapeutic means to treat diabetes. Our overarching hypothesis is that Myc is critical for adaptive ?-cell growth and function, and reversing Myc resistance in the T2D-prone or metabolically-stressed aged ?-cell can lead to an enhanced adaptive response. We will test our hypothesis by completing the following specific aims: 1) To elucidate how nutrients physiologically upregulate Myc in ?-cells and whether Myc upregulation is required for adaptive glucose and ?-cell homeostasis in insulin resistance; 2) To determine the physiological role of Myc on insulin secretion and mitochondrial bioenergetics in the ?-cell; and, 3) To uncover and modify the mechanisms impairing Myc action in the metabolically-stressed, aged, and T2D ?-cells. These studies will deliver unprecedented insight into how Myc is regulated by nutrients, how Myc regulates ?-cell function and how to overcome Myc resistance in the metabolically-stressed aged ?-cell, which will provide a crucial basic platform for designing and testing novel therapeutic strategies for the treatment of diabetes.